The jury is in: p73 is a tumor suppressor after all: Figure 1.

Abstract

While p53 has been extensively characterized as a tumor suppressor, it has been more difficult to determine whether p63 and/or p73 play a similar role. Every system in which these family members have been studied, from cells to animal models to human tissues, seems to create more questions than answers. Tomasini and colleagues (pp. 2677-2691) demonstrate that one isoform of p73 is responsible for preventing tumor formation in vivo, providing critical validation of an isoform-based model of p73 function. The p53 family: three genes, six promoters, 50 isoforms, and counting Although p53, p63, and p73 share similar domain architecture and sequence identity, their differences in vivo are striking. While p53 is frequently mutated during tumorigenesis (in over 50% of human tumors), p63 and p73 are rarely mutated (Moll and Slade 2004). Instead, the p63 locus is amplified in squamous cell carcinomas (Bjorkqvist et al. 1998;Hibi et al. 2000;Massion et al. 2003), and p73 is overexpressed in many tumor types (Moll and Slade 2004). In addition, while p53-null mice develop spontaneous tumors, p63-and p73-null mice die tumor-free from developmental defects (Yang et al. 1999(Yang et al. , 2000. Although p63 and p73 can activate apoptosis in vitro (Jost et al. 1997;Yang et al. 1998), it is clear that they are not classic Knudson-like tumor suppressors like p53.One possibility is that p63 and p73 are tumor suppressors that are inactivated during tumorigenesis by a nonclassical mechanism. Investigation of this possibility is complicated by the complexity of RNA isoforms expressed and the potential for tissue-specific expression. There are nine possible isoforms for p53, six for p63, and 35 for p73 that can arise through a combination of promoter usage and alternative splicing (Bourdon et al. 2005;Murray-Zmijewski et al. 2006). For p63 and p73, two classes of isoforms exist that either contain (TA) or lack (⌬N) the transactivation domain required for full activation of target genes ( Fig. 1; Deyoung .The purported active isoform of p73, TAp73, is of particular interest because it is frequently expressed in human tumors (Deyoung and Ellisen 2007) and can be inhibited by either ⌬Np63 or ⌬Np73 ( Fig. 1; Zaika et al. 2002;Deyoung and Ellisen 2007). In particular, physical ⌬Np63:TAp73 complexes that inactivate TAp73 have now been demonstrated in head and neck squamous cell carcinoma (HNSCC) and basal-like breast cancer cell lines, and evidence suggests these complexes occur in vivo in the corresponding tumor types Rocco et al. 2006;Leong et al. 2007). In addition, tumor-specific forms of p53 have the ability to bind and inhibit p73 ( Fig. 1; Di Como et al. 1999). Thus the ability of ⌬Np63, ⌬Np73, or mutant p53 to inhibit TAp73 may obviate the need for mutation of p73 during tumorigenesis. A single mutation in p53 might decrease both p53 and p73 activities. Similarly, an increase in ⌬Np63 or ⌬Np73 levels could be another means of inactivating TAp73, ultimately preventing TAp73 from engaging in tumor-suppressive activities.Even though r...

p53 isoforms gain functions

“…This concept is widely applied in the extended p53 family, from which three genes express a potential of 50 isoforms, including nine possible isoforms for p53, six for p63 and 35 for p73 (Rosenbluth and Pietenpol, 2008). Thus, the p53, p63 and p73 genes share similar organization, which can each provide a large spectrum of active isoforms with their own unique functions.…”

Induction of Apoptotic Genes by a p73-Phosphatase and Tensin Homolog (p73-PTEN) Protein Complex in Response to Genotoxic Stress

“…p73 and p63 belong to the p53 tumor suppressor family (1)(2)(3)(4). Genetically, both p73 and p63 are components of a p53-dependent network to induce apoptosis (5).…”

Molecular basis of S100 proteins interacting with the p53 homologs p63 and p73

“…Overall, more than 50 isoforms have been identified for the p53 family (Rosenbluth and Pietenpol, 2008), some of them with similar but others even with opposing functions, implying a complicated regulatory network of the p53 family based on splicing. p63 and p73 share great sequence identity with p53, especially in the DNA-binding domain (B 60% identity) (Melino et al, 2003), the transactivation domain (B30% identity) and the tetramerization domain (B40% identity with p53, B70% identity with each other) (Scoumanne et al, 2005;Vilgelm et al, 2008).…”